This proposal will provide Dr. Jermaine Jones with the necessary skills to begin an independent line of research. During the award period, Dr. Jones will accomplish the following training goals: 1) acquire a more comprehensive knowledge of the methodology, safety, and ethics of conducting research with psychoactive substances in humans, 2) gain expertise in contemporary statistical approaches to epidemiological and genetics research, and 3) further develop his grant writing and grant management skills. We will attempt to elucidate the relationship between 3 common gene variants and the abuse liability of oxycodone. Currently, the abuse of prescription opioid medications is a pervasive social problem in the U.S. In an effort to understand some of the variables contributing to prescription opioid abuse, our laboratory has been quantifying the subjective and behavioral effects of commonly abused opioid drugs in humans. The proposed study will first examine the prevalence of polymorphisms of genes that encode the: s opioid receptor (OPRM1), proinflammatory cytokine (IL-12), and cytochrome P450 hepatic metabolizing enzymes (CYP2D6). Data from a variety of sources suggest that functional consequences of each of these particular SNPs may mediate response to opioid drugs and therefore contribute to their abuse liability. Accordingly the second goal of this proposal is to identify the extent to which each of these single participants (150 Heroin Abusers + 150 Prescription Opioid Abusers + 150 Non-Drug Abusers) and collect blood samples for genetic analyses. In a subset of these participants, we will quantify the effects of ascending doses of oxycodone (0, 10, and 30 mg) in a single laboratory session. Ten individuals of each target genotype (OPRM1:118G, IL-12- 511C (or 31T), CYP2D6 null alleles: *3,*4,*5,*6,*7, or*8) from two of the populations sampled (prescription opioid abusers and non-opioid abusers homozygous for each variant of interest) will complete the laboratory session during which we will quantify the subjective effects of oxycodone (see figure below). Our primary dependent measure will be the positive subjective effects of oxycodone (e.g., "I feel a good drug effect"). Secondary dependent measures will include other subjective ratings (e.g., "I feel nauseated"), sum scores on the McGill Pain Questionnaire, cognitive effects, and physiological responses. We hypothesize that there will be a higher frequency of these specific alleles (118G, 12-511C/12-31T, CYP2D6:*3,*4,*5,*6,*7, or*8) among prescription opioid abusers compared to heroin abusers and non-drug abusers, and that the presence of these alleles will be associated with altered subjective response to oxycodone. If the data gained from this investigation support our hypotheses, it may suggest a mechanism by which a single gene polymorphism mediates the abuse potential of certain opioids. Through its combination of structured mentorship, coursework, and innovative research, this award will ensure Dr. Jones'successful transition to an independent investigator. PUBLIC HEALTH RELEVANCE: Previous studies suggest that functional consequences resulting from SNPs in select genes have the potential to alter subjective response to opioid drugs, consequently affecting their abuse liability. This study will examine the prevalence of three gene variants (OPRM1: 118G, Interleukin IL-12: IL-1 2-511 and IL-1B-31, and CYP2D6: *3, *4, *5, *6, *7, *8) among three populations (prescription opioid abusers, heroin abusers, non-drug abusers) and observe for correlations between the presence of these variants and altered subjective and physiological effects of oxycodone. The results of this study should yield important information concerning the relationship between genetic variation and the abuse potential of a commonly abused opioid.